An Open Letter of Academic Discussion to Nobel Laureate Professor Roderick MacKinnon: On the Conformational Dynamics of Potassium-Channel Tetramers

An Open Letter of Academic Discussion to Nobel Laureate Professor Roderick MacKinnon: On the Conformational Dynamics of Potassium-Channel Tetramers

Sun Zuodong
Ya’ou Brain Science Institute of Heilongjiang province

Introduction

The crystal structures of potassium channels resolved by Professor MacKinnon’s team have been incorporated into textbooks worldwide. Yet can static snapshots captured in crystallized states be directly extrapolated to infer the real-world dynamic working mechanisms of potassium channels in living cell membranes? We have raised academic questions on this subject on multiple occasions and received no response to date. This open letter systematizes four core questions for discussion among global peers. This work does not negate crystallographic achievements; it merely poses the question: what exact motions do potassium channels undergo while functioning within living cell membranes?

Abstract

The crystal structures of KcsA, Kv1.2 and other potassium channels solved by MacKinnon’s team represent a milestone for understanding the spatial configuration of potassium-channel tetramers. While acknowledging the scientific value of these static crystal structures, this paper raises questions regarding whether such static structures can be directly used to deduce the authentic dynamic working mechanisms of potassium channels in living cell membranes. According to the prevailing mainstream model, the S6 helices of the tetramer bend at glycine hinges, and the four subunits synchronously radially constrict and expand to close and open the channel. Nevertheless, this dynamic interpretation lacks several key quantitative experimental pieces of evidence: the bending frequency, angular displacement and movement rate of the hinges under physiological membrane potentials remain undetermined; the molecular mechanism enforcing strict synchrony among the four subunits awaits elucidation; whether the prevailing dismissal of overall tetramer rotation about the central pore axis derives from in-situ dynamic observations or pre-set modelling assumptions requires scrutiny; and it remains to be verified whether the hinge-swinging model can quantitatively account for cell-membrane area conservation, unequal transmembrane ion exchange, and achieve consistent agreement with complete electrophysiological data from squid giant axons. As an alternative hypothesis, we propose the “origami windmill model”: the potassium-channel tetramer may rotate in full around its central pore axis. Rotation modulates pore diameter, mediates transmembrane ion transport, and generates detectable electromagnetic signals. The crux of the ongoing debate lies not in static structure per se, but in identifying which specific motions potassium channels perform while operating in living cell membranes. We look forward to discriminating between competing models via in-situ dynamic observations and quantitative kinetic calculations in open, reproducible studies.

Keywords: potassium ion channel; tetramer; conformational dynamics; glycine hinge; origami windmill model; in-situ dynamic observation; cellular electrophysiology

Dear Professor Roderick MacKinnon,

You were awarded the Nobel Prize in Chemistry for your work on potassium-channel crystal structures. These findings feature in cell-physiology textbooks across the globe and have profoundly shaped the scientific community’s understanding of potassium channels. We have previously put forward academic questions concerning the dynamic operational motions of potassium channels within living cell membranes, but have not yet received a reply. We now systematize these questions and publish them in the form of an open letter for collective deliberation by researchers worldwide.

This letter in no way seeks to invalidate the scientific value of the static crystal structures solved by your research group. Our discussion is confined to one point: whether static structural data can directly yield dynamic in-vivo mechanisms. Built upon crystal-structure evidence, the mainstream model posits that S6 helices of the tetramer bend at glycine hinges and undergo synchronous radial constriction and expansion across four subunits to achieve channel gating. Several fundamental questions remain unresolved for this dynamic interpretation. Four core issues are discussed below.

Discussion

The prevailing mainstream model derived from these crystal structures states that S6 helices of the tetramer bend at glycine hinges, and four subunits synchronously constrict and expand radially to switch the channel between closed and open states. Even so, this dynamic account is still unsupported by several critical quantitative experimental observations.

First: Under physiological membrane-potential conditions, what is the reciprocal bending frequency of these hinges? What are the angular displacement and movement speed for each bending event? Can polypeptide backbones sustain high-frequency reciprocal bending cycles without fatigue-induced structural deformation?

Second: Across millions of channel opening-closing cycles, what molecular mechanism maintains perfect synchrony among the four hinge-swinging subunits? If motion of a single subunit lags behind others and distorts the pore architecture, how can the selectivity filter sustain robust potassium-ion selective permeability?

Third: Existing theories rule out the possibility of full-tetramer rotation around the central pore axis. Is this conclusion grounded on in-situ dynamic experimental observations of living membranes, or is it an a-priori assumption embedded during model construction? Static crystallographic snapshots can neither prove rotation nor disprove it.

Fourth: Can the hinge-swinging model quantitatively explain conservation of cell-membrane surface area and unequal transmembrane ion-exchange relationships, while achieving self-consistency against full electrophysiological datasets from squid giant axons?

A crystal structure represents a frozen, instantaneous photograph capturing protein conformation under crystallization conditions. It does not equal the full dynamic picture of how proteins function under physiological conditions. As an alternative hypothesis, we put forward the “origami windmill model”: the potassium-channel tetramer may undergo holistic rotation about its central pore axis. Rotation regulates pore aperture, mediates transmembrane ion translocation, and concurrently produces measurable electromagnetic signals. This model offers a self-consistent explanation for cell-membrane area conservation and unequal ion-exchange phenomena.

The heart of this academic dispute is not what static structure potassium channels adopt, but what motions they execute when carrying out their physiological roles within living cell membranes. Static crystal structures constitute a magnificent starting point, yet they are not the final answer for dynamic functional mechanisms. Given that this dynamic interpretation has entered mainstream textbooks and become consensus within the field, these fundamental questions deserve examination through open, reproducible experiments to advance our understanding of the foundational mechanisms of cellular electrophysiology.

Conclusion

Scientific progress rests on continuous questioning and empirical verification. We sincerely anticipate evidence-based responses from you and fellow researchers addressing the questions raised above. All arguments remain strictly within scientific discourse. Global investigators are encouraged to perform validation work via in-situ dynamic observation and quantitative kinetic simulation to delineate the scope of applicability for each competing model.